Rotavirus infections are ubiquitous throughout mammalian and avian species. The viruses appear to be species-specific although cross-species infections can be produced experimentally and may occur in nature to a limited extent. Infection occurs after ingestion of viral particles and is restricted to the mature absorptive epithelial cells on the villi of the small intestine. Multiplication of rotaviruses within these cells results in lysis, and eventual loss of normal villous structure. Copious acute watery diarrhea occurs as a result of intestinal damage and replacement of absorptive cells by secreting cells from the villous crypts.
Viral gastroenteritis resulting from rotavirus infection is a common cause of epidemic diarrhea in infants from 6 to 24 months of age. Untreated rotavirus diarrhea in young children can be rapidly fatal. The recovery phase in some young children can be very protracted (involving villous atrophy associated with lactose intolerance) and can lead to or exacerbate existing malnutrition (Bishop, R. F. (1993) Vaccine 11:247-254). In fact, rotaviruses appear to be responsible for at least one half of the cases of infantile diarrhea that require hospitalization, and have been estimated to cause 500,000 to 1,000,000 human deaths worldwide each year.
Rotavirus has occasionally been reported as a cause of disease in miliary populations, in hospital workers, and as a cause of travelers' diarrhea. The most common setting for adult disease is that associated with parenting infected infants. Approximately 50% of parents experience rotavirus infection at the time of infant rotavirus disease; one-third of these adult infections are symptomatic (Offit, P. A. and Clark, H. F. (1995) In: Principles and Practices of Infectious Diseases, 4th ed., Mandell, G. L. et al., pp. 1448-1455) and references cited therein). Moreover, rotaviruses are known to cause diarrhea in agriculturally valuable animals such piglets, lambs, and foals, as well as in other animals such as rabbits, deer, and monkeys.
Currently, viral gastroenteritis therapy is limited to supportive measures, since there are no effective antiviral agents available for specific treatment. Prevention of rotavirus illness would be a major contribution to reduction of morbidity from gastroenteritis (Joklik, W. K., ed., Virology, 2nd. ed. (1985), Appleton-Century-Crofts, Norwalk, Conn., pp. 236-238).
Vaccination with inactivated or attenuated organisms or their products has been shown to be an effective method for increasing host resistance and ultimately has led to the eradication of certain common and serious infectious diseases. The use of vaccines is based on the stimulation of specific immune responses within a host.
Rotavirus vaccine development began with tests in children using live, attenuated vaccines from animal rotavirus strains. Two candidate vaccines, RIT4237 and WC3, both bovine serotype 6 viruses, have progressed to field trials (Estes, M. K. and Cohen, J. (1989), Microbiol. Rev. 53:410-449). The bovine strain RIT 4237 showed good efficacy when tested initially in developed countries, but failed to provide protection when tested in developing countries, and has been removed from further testing (Estes, M. K. and Cohen, J. (1989), supra).
Effective vaccines have been developed for relatively few of the infectious agents that cause disease in domestic animals and man. This reflects technical problems associated with the growth and attenuation of virulent strains of pathogens.
Other approaches to the development of candidate vaccines include "reassortants," which contain a single gene encoding the outer capsid glycoprotein from human virus serotypes on a rhesus rotavirus background. Such reassortant vaccines have been produced as potential vaccines to induce homotypic immune response to the four human serotypes (Midthun et al., J. Virol. (1985) 53:949-954; and Estes M. K. and Cohen, J. (1989), supra).
Group A rotaviruses contain seven structural proteins. Of these, the two outer capsid proteins, VP4 and VP7, appear to be the major proteins that induce humoral and cellular immune responses (Estes, M. R. and Cohen, J. (1989) supra; and Dharakul, R. et al. (1991) J. Virol. 65:5928-5932).
VP7 has been the subject of experimental vaccine studies because it is the most abundant outer capsid protein, accounting for approximately 30% of the total virion protein, compared to 1.5% for VP4 (Estes M. R. and Cohen, J. (1989), supra). However, inoculation with vaccinia or adenovirus recombinant virus containing a gene encoding a recombinant VP7.sub.SC gene, or a wild type SA-11 VP7 gene did not elicit protection against homologous rotavirus challenge in an adult mouse model (Dormitzer, P. et al. (1993) Abstr. IXth Intl. Congress of Virology, W21-2, p. 43; and Audio Tape, Dormitzer, P. et al. (Aug. 10, 1993) IXth Intl. Congress of Virology, Workshop W21).).
The major component of the inner capsid, VP6, is antigenically conserved among different serotypes of group A rotaviruses infecting animals, birds, and humans (Bellamy A. R. and Both, G. W., Adv. Virus Res. (1990) 38:1-43; Estes, M. (1991) In: Fundamental virology, 2nd edn, Fields B. N. and Knipe, D. M., eds., pp. 619-642). VP6 is highly immunogenic and antigenic (Estes, M. R. and Cohen, J. (1989), supra) but, paradoxically, does not generate neutralizing antibodies when assayed in vitro. VP6 coding sequence cloned into a vaccinia virus vector and administered to adult mice did not protect against rotavirus infection (Dormitzer, P. et al. (1993) Abstr. IXth Intl. Congress of Virology, W21-2, p. 43; and Audio Tape, Dormitzer, P. et al. (Aug. 10, 1993) IXth Intl. Congress of Virology, Workshop W21). Further, monoclonal antibodies to VP6 do not protect infant mice against rotavirus diarrhea (Riepenhoff-Talty, M. et al. (1987) Adv. Exp. Med. Biol. 216B:1015-1023).